1. Field of the Invention
The present invention relates to novel polypeptides that activate p53 and the polynucleotides encoding these p53 activator peptides. The present invention also relates to pharmaceutical compositions comprising the p53 activator peptides as well as methods of treating abnormal conditions, such as malignant tumors, with the methods comprising administering the pharmaceutical compositions of the present invention to a subject in need of treatment thereof.
2. Background of the Invention
p53 is best known as a tumor suppressor that transcriptionally regulates, in response to cellular stresses such as DNA damage or oncogene activation, the expression of various target genes that mediate cell-cycle arrest, DNA repair, senescence or apoptosis. Loss of p53 activity—either by somatic mutation of the TP53 gene or by functional inhibition of the p53 protein—is a common feature of human tumors. In fact, it is estimated that 50% of human tumors carry loss-of-function mutations in TP53, many of which are associated with malignant progression, poor prognosis and resistance to treatment.
In many other tumors, however, p53 is present in its wild-type form. In these tumors displaying normal p53 function and levels, high levels of negative regulators of p53 such as the E3 ubiquitin ligase MDM2 and its homolog MDMX (also known as MDM4) impede p53-induced growth inhibitory and apoptotic responses. MDM2 primarily controls p53 stability by targeting the tumor suppressor protein for ubiquitin-mediated constitutive degradation by the proteasome, whereas MDMX mainly functions as an effective transcriptional antagonist of p53 that blocks its ability to regulate responsive genes expression. Gene amplification and over-expression of MDM2 and MDMX, found in a significant fraction of cancers without concomitant p53 mutation, correlate to p53 inactivation and tumor survival. Both in vitro and in vivo data demonstrate that inhibition of the p53-MDM2/MDMX interactions by MDM2/MDMX antagonists re-activates the p53 pathway and selectively kills tumor cells in a p53-dependent manner. Acting synergistically in tumor cells to inactivate the p53 pathway, MDM2 and MDMX are among the most promising molecular targets for anticancer therapy.
There exist two major classes of antagonists that target the p53-binding domain of MDM2/MDMX, i.e., low molecular weight, non-peptidic compounds and peptide inhibitors. Small molecules, by virtue of their of small size, low price, oral availability, and ability to cross membranes, are traditionally preferred drug candidates. Peptides, on the other hand, can be more potent, of higher specificity and of lower toxicity. Two major drawbacks of peptides, however, severely limit their therapeutic value. Peptides generally exhibit excessive backbone flexibility and poor membrane permeability, both of which can hinder their use as a practical alternative to small molecules. Conformational flexibility of a peptide not only sacrifices its binding affinity for target protein due to entropy loss, but also contributes to its proteolytic susceptibility or poor in vivo stability.
What is needed in the art, therefore, is a practical alternative to small molecule treatment of tumors that exhibit normal p53. The present invention relates to derivatives of the 31-amino acid residue toxin BmBKTx1 from the venom of the Asian scorpion Buthus martensi Karsch as an ideal template for structure-based rational design of a novel class of MDM2/MDMX antagonists. The toxin derivatives could offer improved potency, specificity, stability, and membrane permeability over presently available treatments.